Clinical Care/Education/Nutrition/Psychosocial Research
O R I G I N A L
A R T I C L E
Serum Carotenoids and Fat-Soluble
Vitamins in Women With Type 1
Diabetes and Preeclampsia
A longitudinal study
MADONA AZAR, MD1
ARPITA BASU, PHD2
ALICIA J. JENKINS, MD1,3
ALISON J. NANKERVIS, MD4
KRISTIAN F. HANSSEN, MD5,6,7
HANNE SCHOLZ, PHD5,7
TORE HENRIKSEN, MD5,7
SATISH K. GARG, MD8
SAMAR M. HAMMAD, PHD9
JAMES A. SCARDO, MD10
CHRISTOPHER E. ASTON, PHD11
TIMOTHY J. LYONS, MD1,11
OBJECTIVE—Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among
women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy
are therefore of interest.
RESEARCH DESIGN AND METHODS—Maternal serum carotenoids (a- and b-carotene,
lycopene, and lutein) and vitamins A, D, and E (a- and g-tocopherols) were measured at first
(12.2 6 1.9 weeks [mean 6 SD], visit 1), second (21.6 6 1.5 weeks, visit 2), and third (31.5 6
1.7 weeks, visit 3) trimesters of pregnancy in 23 women with type 1 diabetes who subsequently
developed PE (DM PE+) and 24 women with type 1 diabetes, matched for age, diabetes duration,
HbA1c, and parity, who did not develop PE (DM PE2). Data were analyzed without and with
adjustment for baseline differences in BMI, HDL cholesterol, and prandial status.
RESULTS—In unadjusted analysis, in DM PE+ versus DM PE2, a-carotene and b-carotene
were 45 and 53% lower, respectively, at visit 3 (P , 0.05), before PE onset. In adjusted analyses,
the difference in b-carotene at visit 3 remained significant. Most participants were vitamin D
deficient (,20 ng/mL), and vitamin D levels were lower in DM PE+ versus DM PE2 throughout
the pregnancy, although this did not reach statistical significance.
CONCLUSIONS—In pregnant women with type 1 diabetes, low serum a- and b-carotene
were associated with subsequent development of PE, and vitamin D deficiency may also be
implicated.
Diabetes Care 34:1258–1264, 2011
P
reeclampsia (PE) is defined as newonset hypertension and proteinuria
during pregnancy. PE is a major cause
of maternal and infant morbidity and
mortality, and its incidence is increased
approximately fourfold by the presence
of maternal type 1 diabetes (1,2). Placental
oxidative stress is implicated in the
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
From the 1Harold Hamm Oklahoma Diabetes Center and Section of Endocrinology and Diabetes, University of
Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; the 2Department of Nutritional Sciences,
Human Environmental Sciences, Oklahoma State University, Stillwater, Oklahoma; the 3Department of
Medicine, The University of Melbourne, St Vincent’s Hospital, Melbourne, Victoria, Australia; the 4Diabetes
Service, The Royal Women’s Hospital, Melbourne, Victoria, Australia; the 5Department of Gynecology and
Obstetrics, Oslo University Hospital, Oslo, Norway; the 6Department of Endocrinology, Oslo University
Hospital, Oslo, Norway; the 7Institute of Clinical Medicine, University of Oslo, Oslo, Norway; the 8Barbara
Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, Colorado;
the 9Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina,
Charleston, South Carolina; the 10Spartanburg Regional Medical Center, Spartanburg, South Carolina; and
the 11General Clinical Research Center, Oklahoma University Health Sciences Center, Oklahoma City,
Oklahoma.
Corresponding author: Timothy J. Lyons, [email protected].
Received 14 November 2010 and accepted 3 March 2011.
DOI: 10.2337/dc10-2145
M.A. and A.B. contributed equally to this work.
© 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/
licenses/by-nc-nd/3.0/ for details.
1258
DIABETES CARE, VOLUME 34, JUNE 2011
pathogenesis of PE (3,4), and compared
with the general population, women with
type 1 diabetes may be particularly prone
to and affected by impaired antioxidant
status. Any alterations in maternal antioxidant status in pregnancy are therefore
of interest. Risk for PE has also been associated with vitamin D deficiency, perhaps mediated through sequelae such as
immune dysfunction, inflammation, and
hypertension (5,6).
Several cross-sectional PE studies
have been performed, mostly in nondiabetic women. Altered levels of carotenoids (a- and b-carotene, lycopene, and
lutein) have been reported (7). Mikhail et al.
(8) found decreased maternal b-carotene
levels in PE, but other studies were not
confirmatory (9,10). Vitamin A, or retinol,
is an essential fat-soluble vitamin with
physiologic functions in mammalian reproduction (11). Cross-sectional studies in
nondiabetic women with and without PE
report both lower (9) and higher (10) vitamin A levels. Vitamin E or a-tocopherol,
which has antioxidant functions, has been
reported to be lower (8,12), higher (9,10),
or similar (13) between PE and normotensive nondiabetic pregnancies.
There are some longitudinal PE studies, although none in type 1 diabetes.
Bodnar et al. (5) found that severe vitamin
D deficiency [25(OH)D ,15 ng/mL] in
early pregnancy was associated with a
fivefold increased risk of PE. Halhali et al.
(14) showed that serum 1, 25(OH) 2D
was not altered in pregnant women who
subsequently developed PE. In a longitudinal study of nondiabetic women with a
risk of high PE, Chappell et al. (15) found
no significant differences in a-tocopherol
concentrations.
Thus, longitudinal studies are few,
and cross-sectional studies are not informative on the temporal relationship between antioxidant status and subsequent
PE. Furthermore, there are no prospective
data relating serum carotenoids, fat-soluble
vitamins, and PE in diabetes.
We report a multicenter prospective study examining differences in
care.diabetesjournals.org
Azar and Associates
Table 1—Clinical profiles of 47 type 1 diabetic and 20 nondiabetic participants
Diabetic
N
Age (years)
BMI (kg/m2)
Alcohol use (%)
None
Stopped during pregnancy
Smoking (%)
No
Quit because of pregnancy
First pregnancy (%)
Gravida (n)
Para (n)
Abortus (n)
Age at diabetes onset (years)
Duration of diabetes (years)
HbA1c (%)
Blood pressure (mmHg)
Systolic
Diastolic
Microalbumin (mg/dL)
Total cholesterol (mg/dL)
HDL cholesterol (mg/dL)
LDL cholesterol (mg/dL)
Triglycerides (mg/dL)
Gestational age (weeks)
Visit 1
Visit 2
Visit 3
Term
Nondiabetic
P value: DM2 vs.
DM PE2
No PE (PE2)
P value: DM PE2 vs.
DM PE+
PE (PE+)
20
31.7 6 4.6
23.6 6 3.7
0.17
0.41
24
29.9 6 3.8
24.6 6 4.1
0.31
0.025
23
28.5 6 5.6
28.0 6 5.8
0.55
25
58
0.39
18
68
11*
68
100*
0
55
1.7 6 1.0
0.5 6 0.9
0.2 6 0.4
—
—
5.3 6 0.3
,0.0001
88
4
75
1.3 6 0.7
0.2 6 0.5
0.1 6 0.3
15 6 8
15 6 7
6.7 6 1.0
0.69
0.26
0.99
0.91
0.91
0.065
0.32
0.13
91
5
76
1.3 6 0.7
0.2 6 0.5
0.1 6 0.4
12 6 6
17 6 7
7.3 6 1.2
112 6 9
67 6 8
0.47 6 0.17
187 6 26
81 6 22
88 6 30
94 6 34
0.35
0.24
0.58
0.22
0.63
0.22
0.076
109 6 10
64 6 8
0.43 6 0.20
176 6 34
84 6 18
77 6 28
75 6 31
0.27
0.27
0.12
0.54
0.035
0.10
0.17
113 6 12
67 6 9
1.03 6 1.78
182 6 28
74 6 14
91 6 28
87 6 24
12.6 6 1.7
21.5 6 1.2
31.2 6 1.1
39.2 6 1.5
0.56
0.97
0.80
0.013
12.3 6 1.7
21.4 6 1.2
31.3 6 1.5
38.0 6 1.4
0.98
0.15
0.39
0.036
12.3 6 2.1
22.1 6 1.7
31.7 6 1.7
37.2 6 1.2
0.55
0.57
0.24
0.18
0.86
Values are means 6 SD. Measurements refer to visit 1 unless otherwise indicated. P values , 0.05 are denoted in boldface. *For these data, P value refers to combined
percentage (i.e., “none” and “stopped during pregnancy,” or “no” and “quit because of pregnancy”).
serum carotenoids, vitamins A (retinol),
D [25(OH)D], and E (tocopherols) between women with type 1 diabetes with
and without subsequent PE. Levels were
measured in each trimester of pregnancy
and before PE onset. Our study evaluated the temporal association of vitamin
and antioxidant provitamin levels with PE
in type 1 diabetes.
Because our major goal was to compare
pregnant women with type 1 diabetes who
subsequently developed PE with those
who did not, our primary comparison is
between these two groups. We also included healthy, normotensive, nondiabetic pregnant women to obtain reference
values during pregnancy, and for illustrative purposes we report some secondary
analyses using their data.
RESEARCH DESIGN AND
METHODS—This is a substudy of a
previously described prospective cohort
care.diabetesjournals.org
of 151 non-Hispanic white women with
type 1 diabetes and 24 nondiabetic subjects
enrolled during the first trimester of pregnancy and followed until delivery (16).
Clinical data and specimens were collected at each trimester (visit 1: 12.2 6
1.9 weeks; visit 2: 21.6 6 1.5 weeks;
and visit 3: 31.5 6 1.7 weeks of gestation
[mean 6 SD]; no overlap) and at term
(37.6 6 2.0 weeks). Visit 3 was before
PE onset. Subjects were requested to fast
overnight, actual prandial status was
recorded, and serum and urine were obtained before any exogenous insulin administration. The study was approved by
the institutional review boards of participating centers in Norway, Australia, and
the U.S. Exclusion criteria were renal impairment (including microalbuminuria),
cardiovascular disease, hypertension, or
other significant medical problems prepregnancy or at visit 1. PE was defined
as new-onset hypertension (.140/90
mmHg) after 20 weeks’ gestation in a previously normotensive woman, accompanied by proteinuria (.300 mg/24 h). Of
the 26 diabetic PE (DM PE+) cases in the
larger cohort (16), samples from 23 were
available for this substudy because of sample attrition. Of 26 DM PE2 cases
matched on the basis of age, diabetes duration, HbA1c, and parity, samples from
24 were available for this study (sample
attrition). For reference values, 20 of 24
pregnant, nondiabetic, non-PE women
(DM2) were also studied (3 were previously excluded as described [16]; 1 additional exclusion due to sample attrition).
Laboratory analyses
Procedures have been detailed (16). Serum carotenoids, retinol, and tocopherols
were measured by high-performance liquid chromatography (HPLC) using a
modified combined version of methods
of Lee et al. (17) and Karppi et al. (18).
DIABETES CARE, VOLUME 34, JUNE 2011
1259
Carotenoids, vitamins, and preeclampsia
Serum vitamin D [25(OH)D] was measured by HPLC/tandem mass spectrometry through Quest Diagnostics Co. (19).
Briefly, 200 mL serum was deproteinized with 200 mL ethanol-butylated hydroxytoluene containing 50 mL internal
standard cocktail, vortexed, extracted
(1,000 mL n-hexane, 60 s), dried (nitrogen, 10 min), and reconstituted in 200 mL
ethanol-butylated hydroxytoluene solution. Then, 50 mL was injected onto a
4.6-mm C-18 Ultrasphere ODS HPLC
column (Beckman Coulter, Inc., Danvers,
MA) and eluted (flow rate 0.8 mL/min)
with an isocratic solvent (methanol,
60%; acetonitrile, 20%; and dichloromethane, 20%). The HPLC system included
a 515 pump, 2996 photodiode array
detector, and a Rheodyne 7725i manual
injector (Waters, Milford, MA). Data acquisition was via Waters Empower data software. Interassay coefficient of variation
for pooled quality samples was #10%.
All assays were performed by operators
masked to sample clinical status.
Statistics
The primary analyses compared DM PE+
with DM PE2. A secondary analysis evaluated differences between DM PE2 and
nondiabetic non-PE control subjects
(DM2). Carotene and tocopherol levels
were analyzed both with and without correction for total lipids (cholesterol + triglyceride). Minimum differences between
DM PE+ and DM PE2 (n $20/group)
could be detected with 80% power as follows: lutein: 0.4 mmol/L; a-tocopherol:
5.4 mmol/L; vitamin A: 0.18 mmol/L;
vitamin D: 3.08 mg/L. Results are reported (Table 1) as means (6 SD) or, for
non-normally distributed measures (per
Shapiro-Wilks test), were transformed
logarithmically and reported as geometric means (95% CI) (all carotenoids [except lutein], g-tocopherol, and a- or
g-tocopherol:lipid ratios). Differences
between groups were analyzed by Student
t test for continuous measures and x2 test
for categoric measures. Analyses were
performed with and without inclusion
of parameters that differed between DM
PE+ and DM PE2 (BMI, HDL cholesterol),
and prandial status, as covariates. Microsoft
Excel 2007 (Microsoft Corp., Redmond,
WA) and SPSS for Windows 15.0 (SPSS
Inc., Chicago, IL) were used.
RESULTS—As shown in Table 1, at
baseline, the diabetic groups were comparable except for higher BMI and lower HDL
cholesterol in DM PE+ versus DM PE2.
1260
DIABETES CARE, VOLUME 34, JUNE 2011
Serum b-carotene was 37% lower at
visit 1 (P , 0.05), and a- and b-carotene
were 45 and 53% lower, respectively, at
visit 3, in DM PE+ versus DM PE2 (P ,
0.05) (Fig. 1A and B), although after adjustment for covariates, only b-carotene
at visit 3 remained significant. Serum lutein levels were similar in DM PE+ versus
DM PE2 at all visits (Fig. 1C); lycopene
was 52% higher in DM PE+ versus
DM PE2 at visit 2 (P , 0.05) (Fig. 1D).
Serum lutein was lower at visits 1 and 2
in DM PE2 versus DM2 (Fig. 1C; P ,
0.05). Differences in lutein and lycopene were not affected by the covariate
analysis.
Serum vitamin A levels did not differ
significantly between the diabetic groups
at any visit (Fig. 2A), but were lower in
DM PE2 versus DM2 at visits 2 and 3
(Fig. 2A; P , 0.05). Consideration of covariates had no effect.
Figure 1—Longitudinal changes in (A) a-carotene, (B) b-carotene, (C) lutein, and (D) lycopene
during gestation. Values are geometric means for a-carotene, b-carotene, and lycopene, and
arithmetic means for lutein. Error bars show the 95% CI for the mean. Three groups of participants are shown; white circle, dashed line: DM PE2 (n = 24); black circle, solid line: DM PE+
(n = 23); white square, dotted lines: DM2 (nondiabetic control subjects, n = 20). Except lutein, all
values were log-transformed before testing for significant differences. Values significantly (P ,
0.05) different between DM PE2 and DM PE+ groups are indicated with an asterisk (*) and
between DM PE2 and DM2 groups are indicated with a double dagger (‡). After adjustment for
covariates (BMI, HDL cholesterol, and prandial status), differences in a-carotene at visit 3 and
b-carotene at visit 1 were no longer significant (P = 0.09 and 0.12, respectively).
care.diabetesjournals.org
Azar and Associates
Vitamin D [25(OH)D] insufficiency,
deficiency, and severe deficiency were
defined as ,30, ,20, and ,15 ng/mL,
respectively (20,21). Mean 25(OH)D
levels did not differ significantly between
DM PE+ and DM PE2 groups, although
there was a slight trend toward lower
levels in DM PE+ throughout pregnancy
(Fig. 2B). Also, women with type 1 diabetes in general, and those who developed
PE in particular, were more likely to be
vitamin D deficient or severely deficient
than the nondiabetic group, and the relative risk of PE associated with vitamin D
deficiency was increased, although not
significantly at any visit (Table 2). Of
relevance to vitamin D, there were no
differences between groups in the seasons
of sample collection (data not shown), and
all enrolled participants were Caucasian.
Unadjusted a-tocopherol levels were
;18% higher in DM PE+ versus DM PE2
at visit 2 (Fig. 2C; P , 0.05), whereas
g-tocopherol was similar in all groups
at all visits (Fig. 2D). Mean serum
a-tocopherol was lower in DM PE2 versus DM2 only at visit 2 (Fig. 2C; P , 0.05).
No differences were noted for g-tocopherol
at any visit (Fig. 2D). Covariate analysis
did not affect significance.
Because carotenes and tocopherols
circulate primarily within lipoproteins,
levels were adjusted for serum total lipids
(Fig. 3). Lipid-adjusted carotenes were
lower in DM PE+ than DM PE2 at visit
1 (b-carotene only) and visit 3 (both carotenes) (Fig. 3A and B; P , 0.05). Again,
after inclusion of covariates, only b-carotene
at visit 3 remained significant. Adjusted
lycopene and lutein levels showed no differences between groups at any visit (data
not shown). By comparing DM PE2 with
DM2, adjusted a- and b-carotenoids
were not significantly different, but they
tended to decline with gestational age
in both groups. Lipid-adjusted a- and
g-tocopherols did not differ between DM
PE+ and DM PE2, or between DM2 and
DM PE2, although a-tocopherol trended
downward in all groups during pregnancy (Fig. 3C). Differences in tocopherol:
lipid ratios were not affected by covariate
analysis.
Figure 2—Longitudinal changes in (A) retinol, (B) vitamin D (cholecalciferol), (C) a-tocopherol,
and (D) g-tocopherol (log transformed) during gestation. Values are arithmetic means for retinol,
cholecalciferol, and a-tocopherol, and geometric means (95% CI) for g-tocopherol. Group and statistical symbols are as in Fig. 1. Adjustment for covariates had no effect on significance. Statistically
significant differences between visits were seen for (C) a-tocopherol in DM PE+ between gestational
age 12 and 22 weeks, and in DM PE2 between gestational age 22 and 32 weeks (P , 0.05).
CONCLUSIONS—In a prospective
study of pregnant women with type 1
diabetes, we demonstrated lower serum
carotenoids, especially b-carotene, in affected versus unaffected women before
PE onset. We also observed a high prevalence of vitamin D insufficiency, most frequently in women who developed PE.
Relative to early pregnancy, there was
also a downward trend in lipid-adjusted
carotenoids and tocopherols in the third
trimester, perhaps representing antioxidant reserve depletion. This decline occurred because total cholesterol and
triglycerides increased by 1.5- and twofold, respectively, between visits 1 and 3
(not shown) in all groups. We have previously shown that pregnant women with
type 1 diabetes are already “primed” for
PE by having elevated levels of endoglin
(16), and in this setting, antioxidant depletion may trigger PE.
We identified significantly lower serum b-carotene, and by some analyses,
lower a-carotene, in pregnant women
with type 1 diabetes who subsequently
developed PE versus those who did
not. Our longitudinal data, particularly
between-group differences in serum carotenoids (DM PE+ vs. DM PE2) in the
third trimester, concur with existing
cross-sectional studies, performed later
in pregnancy in nondiabetic women,
that show lower circulating carotenoids
in PE (8,10). b-Carotene also possesses
pro-vitamin A activity (22), and we postulate that the low b-carotene in the
third trimester could be explained by increased endogenous antioxidant consumption due to elevated oxidative stress or
care.diabetesjournals.org
DIABETES CARE, VOLUME 34, JUNE 2011
1261
1262
PE+: PE (n = 23); PE2: no PE (n = 24); DM2: nondiabetic, non-PE pregnant control subjects (n = 20). Reference group for relative risk in all cases comprises women in whom vitamin D level is sufficient (.30 ng/mL). RR,
relative risk.
1.5 (0.3–7.7)
1.9 (0.3–11.0)
2.1 (0.4–12.4)
75
45
30
91
52
30
96
61
39
1.4 (0.3–7.9)
1.8 (0.3–10.8)
1.8 (0.3–11.2)
79
53
26
90
70
45
95
60
30
2.1 (0.4–11.8)
2.2 (0.4–12.3)
2.5 (0.4–14.2)
84
37
0
87
65
22
96
78
39
,30
,20
,15
DM PE+ (%) DM PE2 (%) DM2 (%)
RR (95% CI)
DM PE+ (%) DM PE2 (%) DM2
RR (95% CI)
Visit 3
Visit 2
Visit 1
Vitamin D
level (ng/mL) DM PE+ (%) DM PE2 (%) DM2 (%)
Table 2—Percentage of participants who are vitamin D [25(OH)D] insufficient (<30 ng/mL), deficient (<20 ng/mL), or severely deficient (<15 ng/mL), and relative risk
of PE associated with low vitamin D levels (<30, <20, and <15 ng/mL) in diabetic participants
RR (95% CI)
Carotenoids, vitamins, and preeclampsia
DIABETES CARE, VOLUME 34, JUNE 2011
Figure 3—Longitudinal changes in ratios (A) a-carotene: total lipids, (B) b-carotene: total
lipids, (C) a-tocopherol: total lipids, and (D) g-tocopherol: total lipids, during gestation. Values
are geometric means (95% CI). Ratios are expressed as serum tocopherol and carotenoid molarity
(mmol/L) to total lipid mass (serum total cholesterol and triglycerides) (mg/dL). Group and
statistical symbols are as in Fig. 1. After adjustment for covariates (BMI, HDL cholesterol, and
prandial status), differences in a-carotene at visit 3 and b-carotene at visit 1 were no longer
significant (P = 0.08 and 0.07, respectively).
increased conversion to vitamin A to
compensate for low vitamin A levels. In
our study, low vitamin A levels in women
with type 1 diabetes in the first trimester
are comparable to those previously reported (9,10) and to levels in U.S. adult
women (23). Thus, although not statistically significant, decreasing vitamin A
levels between the second and third trimesters in women with type 1 diabetes
could promote PE.
Vitamin D deficiency, an increasingly prevalent condition in women of
childbearing age (20), has been associated with PE in a large prospective study
(5). We found that the majority of our
participants, regardless of geographic
location (which included sunny regions
such as Oklahoma, South Carolina, and
Australia), were vitamin D deficient.
Levels did not differ between sites. We
lack information on dietary intake or
ultraviolet light exposure. The women
with type 1 diabetes as a whole had lower
levels than our nondiabetic reference
group (data not shown). The reason is
unclear. Occult celiac disease, which
may cause vitamin D malabsorption, is
prevalent (5–10%) in type 1 diabetes
(24) and could be contributory.
Links between vitamin D deficiency
and PE are unclear. Hyppönen (6) proposed an immune hypothesis, whereby
local disruption of vitamin D status promotes loss of maternal–fetal immune
tolerance and immune maladaptation.
care.diabetesjournals.org
Azar and Associates
Although this is intriguing, it has yet to be
established as a cause for PE in humans.
Another possibility is diminished placental 1a-hydroxylase activity, which occurs
in PE (25) and lowers local and circulating
1,25(OH)2D.
In agreement with Williams et al. (10),
our study does not support a relationship
between serum a- and g-tocopherols
and PE, although the decline in adjusted
a-tocopherol levels throughout the pregnancy might have a permissive effect in
women already predisposed. The mean
first trimester serum a-tocopherol values
(25–30 mmol/L) in the women with type 1
diabetes in our study were comparable to
normal values in U.S. adults and above the
threshold indicating vitamin E deficiency
(,11.6 mmol/L) (23).
Our study has several limitations.
The findings merit confirmation in larger
prospective studies involving diabetic
and nondiabetic women. Furthermore,
confounding due to certain group differences in this small cohort, although
nonsignificant, cannot be excluded. More
data regarding maternal diet, vitamin
supplement use, and ultraviolet exposure
would have been helpful to dissect cause
and effect. Measures of other antioxidant
vitamins and enzymes would be of interest. Fasting overnight is challenging
for pregnant women with type 1 diabetes, and at each visit, a similar proportion
from each diabetic group (range 2–6 of
23 or 24) attended nonfasting. However,
our conclusions were not substantially
affected by statistical adjustment for
prandial status (as presented) or exclusion
of nonfasting visits (data not shown).
We believe this is the first longitudinal study of the relationship between PE
in pregnant women with type 1 diabetes
and antecedent serum levels of carotenoids and vitamins A, D, and E. We found
that women with type 1 diabetes who
developed PE had lower antecedent serum a- and b-carotene concentrations
than those who did not. Vitamin D insufficiency affected most women with type 1
diabetes, and levels tended to be lower in
those who developed PE. Lipid-adjusted
levels of many of the fat-soluble antioxidants declined during pregnancy. Our
study sample, although small, represented women with type 1 diabetes from
different geographic locations. Further
studies are needed to define whether optimizing fat-soluble antioxidant and vitamin status throughout pregnancy can
reduce the high incidence of PE in those
with type 1 diabetes.
care.diabetesjournals.org
Acknowledgments—This work was supported by a research grant from the Juvenile
Diabetes Research Foundation (1-2001-844),
National Institutes of Health (NIH) (National
Center on Minority Health and Health Disparities) Grant P20-MD-000528-05 to T.J.L.,
NIH (National Center for Research Resources)
Grant M01-RR-1070 to the General Clinical
Research Centers at Medical University of
South Carolina, and NIH Grant M01-RR14467 to Oklahoma University Health Sciences Center.
Support from Novo Nordisk enabled the
participation of the Barbara Davis Diabetes
Center for Childhood Diabetes. No other potential conflicts of interest relevant to this article were reported.
M.A., A.B., and A.J.J. researched data, contributed to discussion, and wrote the article.
A.J.N., K.F.H., H.S., T.H., S.K.G., S.M.H., and
J.A.S. researched data, contributed to discussion, and reviewed the article. C.E.A. researched
data and contributed to discussion. T.J.L. researched data, contributed to discussion, and
wrote the article.
The skilled and dedicated assistance of the
following individuals for their scientific contribution to this article is acknowledged:
Yongxin Yu, Mingyuan Wu, Azar Dashti, and
Kerri May (University of Oklahoma); Torun
Clausen and Bjørg Lorentzen (Oslo University
Hospital); Kathryn M. Menard (University of
North Carolina); and John R. Stanley (Mercy
Health Center, Oklahoma). The following are
acknowledged for technical or clinical assistance: Jill Mauldin and Mary Myers (Medical
University of South Carolina); Jill Cole
and Nancy Sprouse (Spartanburg Regional
Hospital, Spartanburg, SC); Myrra Windau
(University of Colorado); Christine Knight,
Jennifer Conn, Peter England, Susan Hitchcock,
Jeremy Oats, and Peter Wein (Royal Women’s
Hospital, Melbourne); and Julie Stoner and
Lori Doyle (University of Oklahoma). At the
University of Oklahoma, Kenneth Wilson
and Gennadiy Moiseyev assisted with sample
processing and the conduct of laboratory
work.
References
1. Zhu L, Nakabayashi M, Takeda Y. Statistical analysis of perinatal outcomes in
pregnancy complicated with diabetes mellitus. J Obstet Gynaecol Res 1997;23:555–
563
2. Hanson U, Persson B. Outcome of pregnancies complicated by type 1 insulindependent diabetes in Sweden: acute
pregnancy complications, neonatal mortality
and morbidity. Am J Perinatol 1993;10:
330–333
3. Hubel CA. Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol
Med 1999;222:222–235
4. Llurba E, Gratacós E, Martín-Gallán P,
Cabero L, Dominguez C. A comprehensive
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
study of oxidative stress and antioxidant
status in preeclampsia and normal pregnancy. Free Radic Biol Med 2004;37:557–
570
Bodnar LM, Catov JM, Simhan HN,
Holick MF, Powers RW, Roberts JM. Maternal vitamin D deficiency increases the
risk of preeclampsia. J Clin Endocrinol
Metab 2007;92:3517–3522
Hyppönen E. Vitamin D for the prevention of preeclampsia? A hypothesis.
Nutr Rev 2005;63:225–232
Paiva SA, Russell RM. Beta-carotene and
other carotenoids as antioxidants. J Am
Coll Nutr 1999;18:426–433
Mikhail MS, Anyaegbunam A, Garfinkel D,
Palan PR, Basu J, Romney SL. Preeclampsia
and antioxidant nutrients: decreased plasma
levels of reduced ascorbic acid, alphatocopherol, and beta-carotene in women
with preeclampsia. Am J Obstet Gynecol
1994;171:150–157
Zhang C, Williams MA, Sanchez SE, et al.
Plasma concentrations of carotenoids, retinol, and tocopherols in preeclamptic and
normotensive pregnant women. Am J Epidemiol 2001;153:572–580
Williams MA, Woelk GB, King IB, Jenkins L,
Mahomed K. Plasma carotenoids, retinol,
tocopherols, and lipoproteins in preeclamptic and normotensive pregnant
Zimbabwean women. Am J Hypertens
2003;16:665–672
Clagett-Dame M, DeLuca HF. The role of
vitamin A in mammalian reproduction
and embryonic development. Annu Rev
Nutr 2002;22:347–381
Sagol S, Ozkinay E, Ozsxener S. Impaired
antioxidant activity in women with preeclampsia. Int J Gynaecol Obstet 1999;64:
121–127
Hubel CA, Kagan VE, Kisin ER, McLaughlin
MK, Roberts JM. Increased ascorbate radical formation and ascorbate depletion in
plasma from women with preeclampsia:
implications for oxidative stress. Free Radic
Biol Med 1997;23:597–609
Halhali A, Villa AR, Madrazo E, et al.
Longitudinal changes in maternal serum
1,25-dihydroxyvitamin D and insulin like
growth factor I levels in pregnant women
who developed preeclampsia: comparison with normotensive pregnant women.
J Steroid Biochem Mol Biol 2004;89–90:
553–556
Chappell LC, Seed PT, Briley A, et al. A
longitudinal study of biochemical variables in women at risk of preeclampsia.
Am J Obstet Gynecol 2002;187:127–
136
Yu Y, Jenkins AJ, Nankervis AJ, et al. Antiangiogenic factors and pre-eclampsia in
type 1 diabetic women. Diabetologia 2009;
52:160–168
Lee BL, New AL, Ong CN. Simultaneous
determination of tocotrienols, tocopherols,
retinol, and major carotenoids in human
plasma. Clin Chem 2003;49:2056–2066
DIABETES CARE, VOLUME 34, JUNE 2011
1263
Carotenoids, vitamins, and preeclampsia
18. Karppi J, Nurmi T, Olmedilla-Alonso B,
Granado-Lorencio F, Nyyssönen K. Simultaneous measurement of retinol, alphatocopherol and six carotenoids in human
plasma by using an isocratic reversed-phase
HPLC method. J Chromatogr B Analyt
Technol Biomed Life Sci 2008;867:226–
232
19. Quest Diagnostics. Available from http://
www.questdiagnostics.com/hcp/topics/
endo/vitamin_d.html. Accessed 17 March
2011
20. Ginde AA, Sullivan AF, Mansbach JM,
Camargo CA Jr. Vitamin D insufficiency in
1264
DIABETES CARE, VOLUME 34, JUNE 2011
pregnant and nonpregnant women of
childbearing age in the United States. Am J
Obstet Gynecol 2010;202:436.e1–e8
21. Bischoff-Ferrari HA, Giovannucci E,
Willett WC, Dietrich T, Dawson-Hughes B.
Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple
health outcomes. Am J Clin Nutr 2006;84:
18–28
22. Strobel M, Tinz J, Biesalski HK. The importance of beta-carotene as a source of
vitamin A with special regard to pregnant
and breastfeeding women. Eur J Nutr
2007;46(Suppl. 1):I1–I20
23. Tohill BC, Heilig CM, Klein RS, et al.
Nutritional biomarkers associated with
gynecological conditions among US women
with or at risk of HIV infection. Am J Clin
Nutr 2007;85:1327–1334
24. Crone J, Rami B, Huber WD, Granditsch G,
Schober E. Prevalence of celiac disease and
follow-up of EMA in children and adolescents with type 1 diabetes mellitus. J Pediatr
Gastroenterol Nutr 2003;37:67–71
25. Mulligan ML, Felton SK, Riek AE, BernalMizrachi C. Implications of vitamin D
deficiency in pregnancy and lactation. Am
J Obstet Gynecol 2010;202:429.e1–e9
care.diabetesjournals.org